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C H A P T E R 13

CHEMOKINES AND HEMATOPOIETIC CELL TRAFFICKING

Antal Rot, Steffen Massberg, Alexander G. Khandoga, and
Ulrich H. von Andrian

The mammalian immune system has evolved to mount multifaceted signals and control the recruitment of effector leukocytes in infection,
molecular and cellular microbicidal responses tailored and custom- inflammation, tissue injury, and malignancies, whereas the latter
adapted to eliminate an endless variety of infectious agents and, at navigate leukocytes during hematopoiesis in the BM and in the
the same time, remain tolerant to self-antigens. Accomplishing these thymus during initiation of adaptive immune responses in secondary
tasks requires continuous movement of billions of motile immune lymphoid organs and in immune surveillance of healthy peripheral
cells that roam throughout the body along distinct nonrandom traffic tissues. However, it is now clear that such functional distinction is
routes from one tissue to another using blood and lymphatic vessels largely blurred, as many “inflammatory” chemokines are produced
as avenues for rapid access. Migratory pathways characteristic for under physiologic conditions and the expression of “homeostatic”
distinct immune cell subsets are integral parts of their functional chemokines is upregulated in inflammation.
make-up determined in the process of cell differentiation and activa- Chemokine signals are transmitted through specific cell-surface G
tion. During development in the bone marrow (BM) or thymus, or protein–coupled receptors (GPCRs) with seven transmembrane
following stimulation by antigens or pathogen-associated molecules, domains. 19–23 The human chemokine receptor repertoire identified at
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immune cells acquire the expression of characteristic repertoires of present consists of 20 different GPCRs (Table 13.2). The tremen-
cell surface molecules that enable and restrict their migration to dous specificity and plasticity of leukocyte homing and tissue localiza-
defined tissues and microenvironments. For example, naive lympho- tion is largely determined by the interactions of chemokines with
cytes largely disregard inflammatory tissue sites, but migrate efficiently their cognate receptors. Individual leukocyte subsets express charac-
into secondary lymphoid organs. Conversely, innate immune cells teristic fingerprints of chemokine receptors, and each chemokine
and antigen-experienced lymphocytes can respond to inflammation- receptor binds defined sets of chemokines, albeit with various binding
induced traffic cues, although some subsets also enter noninflamed affinities and resulting in a spectrum of downstream of responses,
1–4
lymphoid and nonlymphoid target tissues. Notably, not only from agonism to antagonism. 25,26 Chemokine receptors function as
mature leukocytes but also hematopoietic stem cells (HSCs) and allosteric molecular relays where chemokine binding to the extracel-
progenitor cells, and other rare cell subsets recirculate throughout the lular portion modifies the tertiary structure of the receptor. This
body. 5–13 The characteristic trafficking routes of leukocyte subpopula- allows the intracellular domain of the engaged receptor to bind to
tions are determined by their expression of cell surface adhesion and activate heterotrimeric G proteins. In response, the activated G
molecules and chemoattractant receptors. Chemoattractants are proteins exchange GDP for GTP, and in the process dissociate into
generated in target sites and signal through their cognate receptors Gα and Gβγ subunits. The dissociated Gβγ subunits mediate most
on leukocytes to induce their emigration and directed locomotion chemokine-induced signals by activating different phosphatidylino-
within the tissues. Leukocyte chemoattractants include a number of sitol 3-kinase (PI3K) isoforms, leading to the formation of
lipid mediators, microbial factors, complement fragment 5a and, phosphatidyl-3,4,5-triphosphate (PIP 3 ). PI3K and its product PIP 3
most importantly, members of the chemokine family. This chapter then translocate to the pseudopod at the leading edge of migrating
discusses chemokines as master navigation signals for leukocyte traf- leukocytes, where they colocalize with the small GTPase Rac. 27–30
ficking and then focuses on specific trafficking pathways that direct PIP 3 activates Rac through specific guanine nucleotide exchange
leukocyte subsets to distinct target tissues. factors. 31,32 Rac in turn acts through the downstream effectors p21-
activated kinase and the Wiskott-Aldrich syndrome protein homo-
logue WAVE, which stimulate actin-related protein 2/3. Together,
CHEMOKINES IN CONTROL OF LEUKOCYTE TRAFFICKING this process induces focal polymerization, required for the develop-
ment and forward extension of the pseudopod, a critical step in
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Chemokines (a clipping blend of chemotactic cytokines) are critical leukocyte chemotaxis. The importance of PI3K-dependent signal-
molecular messengers in the complex cellular communication ing for leukocyte chemotaxis is evidenced by the lack of migration of
network used by the immune system. Almost 50 human chemokines myeloid leukocytes to chemokines in mice lacking PI3Kγ. 34–39
have been identified to date (Table 13.1). 14–18 However, due to the Notably, though, distinct signaling pathways or at least other PI3K
existence of different splice variants and enzymatically processed isoforms appear to be involved in the trafficking of immune cells. For
forms the number of individual functionally distinct chemokine example, neutrophil and B-cell migration requires PI3Kδ 42–45 , whereas
molecules is much higher. The two major subclasses of chemokines T-cell chemotaxis is not impaired in PI3K-deficient mice, but depends
are designated CC- or CXC-, depending on the relative position of on the Rac guanine exchange factor DOCK2. 40–42
the two proximal to the N-terminus canonical cysteines, being either Different pathways have been identified that can terminate che-
adjacent or separated by a single amino acid, respectively. XCL1 and mokine signaling through their GPCRs. The Gα subunit possesses
XCL2, and CX3CL1 constitute two additional structural chemokine an intrinsic GTPase activity to hydrolyze GTP. In a negative-feedback
forms with one cysteine and three amino acids between the two loop this GTPase activity allows the Gα subunits to reassociate with
canonical cysteines, respectively. CX3CL1 and another chemokine, the Gβγ subunits, thereby restoring the heterotrimeric G protein to
CXCL16, are associated with a cell membrane via a long spacer its inactive state. In addition, another class of molecules, known as
sequence and anchored by a transmembrane domain; however, both regulators of G protein signaling (RGS), also modulates signaling
these chemokines can be cleaved of their stalks and give rise to through chemokine GPCRs. RGS are a large and diverse protein
functional soluble molecules. All other chemokines are secreted family initially identified as GTPase-activating proteins of heterotri-
proteins of 67 to 127 amino acids. Historically, chemokines have meric G protein Gα-subunits. 43,44 At least some RGS can also influ-
been grouped into functional subfamilies termed inflammatory and ence Gα activity through either effector antagonism by competing
homeostatic chemokines. The former are induced by inflammatory with effector molecules for GTP-bound Gα-subunits or by acting as

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